Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP)

Behavioral Neurogenetics Center, Child Psychiatry Department, Schneider Children's Medical Center of Israel, Petah Tiqwa.
Annals of Neurology (Impact Factor: 9.98). 01/2008; 63(1):40-51. DOI: 10.1002/ana.21243
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ABSTRACT To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior.
This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist.
Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors.
Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders.

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Available from: Scott Hall, Sep 25, 2015
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    • "Hatton et al. [82] suggested that lower levels of fragile X mental retardation protein (FMRP) expression contribute to autistic behavior and intellectual deficits in children with FXS. Gothelf et al. [85] revealed a correlation between lower levels of FMRP, behavioral alterations, and alterations of the size of some brain subdivisions, including increased size of the caudate nucleus but decreased size of the amygdala, superior temporal gyrus, and posterior cerebellar vermis in FXS. A 75% reduction of FMRP expression in vermis and a 50% reduction in the superior frontal cortex (BA9) in adults with idiopathic autism may contribute to both structural abnormalities and the autistic phenotype [86]. "
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    ABSTRACT: IntroductionA total of 38 brain cytoarchitectonic subdivisions, representing subcortical and cortical structures, cerebellum, and brainstem, were examined in 4- to 60-year-old subjects diagnosed with autism and control subjects (a) to detect a global pattern of developmental abnormalities and (b) to establish whether the function of developmentally modified structures matches the behavioral alterations that are diagnostic for autism. The volume of cytoarchitectonic subdivisions, neuronal numerical density, and total number of neurons per region of interest were determined in 14 subjects with autism and 14 age-matched controls by using unbiased stereological methods.ResultsThe study revealed that significant differences between the group of subjects with autism and control groups are limited to a few brain regions, including the cerebellum and some striatum and amygdala subdivisions. In the group of individuals with autism, the total number and numerical density of Purkinje cells in the cerebellum were reduced by 25% and 24%, respectively. In the amygdala, significant reduction of neuronal density was limited to the lateral nucleus (by 12%). Another sign of the topographic selectivity of developmental alterations in the brain of individuals with autism was an increase in the volumes of the caudate nucleus and nucleus accumbens by 22% and 34%, respectively, and the reduced numerical density of neurons in the nucleus accumbens and putamen by 15% and 13%, respectively.Conclusions The observed pattern of developmental alterations in the cerebellum, amygdala and striatum is consistent with the results of magnetic resonance imaging studies and their clinical correlations, and of some morphometric studies that indicate that detected abnormalities may contribute to the social and communication deficits, and repetitive and stereotypical behaviors observed in individuals with autism.
    09/2014; 2(1):141. DOI:10.1186/s40478-014-0141-7
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    • "A variety of neuroanatomical abnormalities are seen in FXS patients including a larger caudate nucleus and hippocampus and a reduced superior temporal gyrus (STG), amygdala, anterior ventral cerebral gray matter, and anterior mid-inferior cerebral gray matter (Hessl et al., 2004; Gothelf et al., 2008). Diffuser tensor imaging found alterations in the frontal-caudate and parietal sensory-motor white matter tracts in FXS patients, which may alter the speed of neural processing or the magnitude of neuronal responses (Barnea-Goraly et al., 2003). "
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    ABSTRACT: Fragile X syndrome (FXS) is an inherited form of intellectual disability and autism. Among other symptoms, FXS patients demonstrate abnormalities in sensory processing and communication. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity in humans with FXS. Consistent with observations in humans, the Fmr1 KO mouse model of FXS also shows evidence of altered auditory processing and communication deficiencies. A well-known and commonly used phenotype in pre-clinical studies of FXS is audiogenic seizures. In addition, increased acoustic startle response is seen in the Fmr1 KO mice. In vivo electrophysiological recordings indicate hyper-excitable responses, broader frequency tuning, and abnormal spectrotemporal processing in primary auditory cortex of Fmr1 KO mice. Thus, auditory hyper-excitability is a robust, reliable, and translatable biomarker in Fmr1 KO mice. Abnormal auditory evoked responses have been used as outcome measures to test therapeutics in FXS patients. Given that similarly abnormal responses are present in Fmr1 KO mice suggests that cellular mechanisms can be addressed. Sensory cortical deficits are relatively more tractable from a mechanistic perspective than more complex social behaviors that are typically studied in autism and FXS. The focus of this review is to bring together clinical, functional, and structural studies in humans with electrophysiological and behavioral studies in mice to make the case that auditory hypersensitivity provides a unique opportunity to integrate molecular, cellular, circuit level studies with behavioral outcomes in the search for therapeutics for FXS and other autism spectrum disorders.
    Frontiers in Cellular Neuroscience 02/2014; 8:19. DOI:10.3389/fncel.2014.00019 · 4.29 Impact Factor
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    • "Several studies have shown that elevated behavior problems in FXS may be associated with factors such as increased cortisol [Hessl et al., 2002], atypical autonomic regulation [Heilman et al., 2011], inadequate levels of oxytocin [Hall et al., 2012], secondary genes [Hessl et al., 2008], or neuroanatomical abnormalities and reduced levels of FMRP (the protein disrupted by FXS) [Gothelf et al., 2007]. "
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    ABSTRACT: Behavior problems are a common challenge for individuals with fragile X syndrome (FXS) and constitute the primary clinical outcome domain in trials testing new FXS medications. However, little is known about the relationship between caregiver-reported behavior problems and co-occurring conditions such as anxiety and attention problems. In this study, 350 caregivers, each with at least one son or daughter with full-mutation FXS, rated one of their children with FXS using the Aberrant Behavior Checklist-Community Version (ABC-C); the Anxiety subscale of the Anxiety, Depression, and Mood Scale; and the Attention/Hyperactivity Items from the Symptom Inventories. In addition to examining family consequences of these behaviors, this study also sought to replicate psychometric findings for the ABC-C in FXS, to provide greater confidence for its use in clinical trials with this population. Psychometric properties and baseline ratings of problem behavior were consistent with other recent studies, further establishing the profile of problem behavior in FXS. Cross-sectional analyses suggest that selected dimensions of problem behavior, anxiety, and hyperactivity are age related; thus, age should serve as an important control in any studies of problem behavior in FXS. Measures of anxiety, attention, and hyperactivity were highly associated with behavior problems, suggesting that these factors at least coincide with problem behavior. However, these problems generally did not add substantially to variance in caregiver burden predicted by elevated behavior problems. The results provide further evidence of the incidence of problem behaviors and co-occurring conditions in FXS and the impact of these behaviors on the family. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1):141-55. DOI:10.1002/ajmg.a.36232 · 2.16 Impact Factor
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